Postmortem pulmonary gas trapping was investigated as an index of in vivo airway obstruction following methacholine inhalation in four different rodent species. Male guinea pigs (Hartley), hamsters (golden Syrian), mice (A/J, BALB/c, and ICR), and rats (Brown-Norway, Fischer 344, Lewis, and Sprague-Dawley) were exposed to aerosols of methacholine or sodium chloride. Maximum excised lung gas volumes (ELGV) of methacholine-exposed guinea pigs, hamsters, mice, and rats were 2.3-8.7 times those of sodium chloride-treated animals. Mean ELGV values of sodium chloride-exposed animals ranged from 1.50 +/- 0.20 ml/kg for guinea pigs to 2.75 +/- 0.20 ml/kg for Brown-Norway rats. Although all species responded to methacholine, guinea pigs were the most responsive, with approximately 1.6 microgram/kg of inhaled methacholine needed to increase ELGV to 200% of control. Compared with guinea pigs, hamsters, mice, and rats were 11- to 1,395-fold less responsive. Although hamsters, mice, and rats are less sensitive than guinea pigs to the airway-obstructive effects of methacholine, pulmonary gas trapping appears useful as a measure of airway responses in these species.

No abstract

Male Hartley guinea pigs were exposed by inhalation to leukotriene B4 (LTB4) and challenged 5 min or 4 h later with bronchoconstrictive aerosols of histamine or the divalent cationic ionophore A23187. Pulmonary gas trapping measured in excised lungs indicated the severity of post-challenge airway obstruction. Airway granulocyte infiltration was scored by an observer who was unaware of animal assignments. Treatment with LTB4 produced a marked influx of eosinophils and neutrophils into tracheal and bronchial airways. Granulocyte scores for LTB4-treated groups were 1.9 to 3.3 times higher than those for vehicle-treated groups at 5 min after exposure and 3.3 to 10.7 times higher at 4 h after exposure. Leukotriene B4 itself did not produce hyperinflation. However, histamine-induced gas trapping was increased 5 min after LTB4 exposure. Histamine responsiveness was unaffected 4 h after LTB4 treatment. In contrast, A23187-induced gas trapping was unaffected at 5 min, but diminished at 4 h after LTB4. Nonchemotactic stereoisomers of LTB4 did not produce granulocyte influx, but did produce altered airway responses similar to those seen for LTB4. We conclude that inhaled LTB4 produces airway granulocyte infiltration in the guinea pig and alterations in airway responsiveness that vary with the challenge stimulus and time after exposure. Alterations in airway responses may result from granulocyte-independent effects of LTB4 and its stereoisomers.

We examined the in vivo actions of LY293111 sodium (2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]pro poxy]phenoxy] benzoic acid sodium salt). Guinea pigs were used to evaluate the effect of this agent on (1) acute airway obstruction produced by intravenous leukotriene B4, (2) pulmonary granulocyte infiltration and delayed onset airway obstruction resulting from a 4-h leukotriene B4 inhalation and (3) lung inflammation after aerosol challenge with the divalent cationic ionophore A23187 (6S-[6alpha(2S*,3S*),8beta(R*),9beta,11alpha]-5- (methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)e thyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazole carboxylic acid). Airway obstruction was quantitated using pulmonary gas trapping measurements and lung inflammation was evaluated by bronchoalveolar lavage (BAL) and histology. LY293111 sodium produced a dose-related inhibition of acute leukotriene B4-induced airway obstruction when administered i.v. (ED50=14 microg/kg) or p.o. (ED50=0.4 mg/kg). In contrast, LY293111 sodium did not inhibit the pulmonary gas trapping caused by aerosols of histamine, leukotriene D4, or the thromboxane mimetic U46619 (15 [(S)-hydroxy11a,9a-(epoxymethano)prosta-5Z,13E-dienoic acid]). Oral LY293111 sodium inhibited leukotriene B4-induced bronchoalveolar lavage granulocyte infiltration and delayed onset airway obstruction at doses as low as 0.3 mg/kg. In A23187-challenged animals, pulmonary inflammation was markedly inhibited at 1 h, but not 2 h and 4 h post-exposure. We conclude that LY293 11 sodium is a selective leukotriene B4 receptor antagonist with potent pulmonary anti-inflammatory activity.

No abstract